(S)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine-di-p-toluoyl-l-tartarate and methods of preparation thereof

ABSTRACT

The invention provides (S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine-Di-p-toluoyl-L-tartarate (DNT-L-pTTA), which can be used as an intermediate in the preparation of duloxetine hydrochloride, processes for the preparation of DNT-L-pTTA, a crystalline form of DNT-L-pTTA, and processes for the preparation of duloxetine hydrochloride form DNT-L-pTTA.

This application claims benefit of U.S. Provisional Application Nos. 60/661,711 filed Mar. 14, 2005, 60/761,905 filed Jan. 24, 2006, 60/771,071 filed Feb. 6, 2006 and 60/773,593 filed Feb. 14, 2006, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to DNT-Di-p-toluoyl-L-tartarate, an intermediate for the synthesis of Duloxetine, and the solid state chemistry of DNT-Di-p-toluoyl-L-tartarate. The present invention also provides processes for converting the DNT-Di-p-toluoyl-L-tartarate into pharmaceutically acceptable salts of duloxetine.

BACKGROUND OF THE INVENTION

Duloxetine HCl is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI), depression, and pain management. Duloxetine hydrochloride has the chemical name (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloric acid salt and the following structure.

Duloxetine, as well as processes for its preparation is disclosed in U.S. Pat. No. 5,023,269 (US '269). EP Patent No. 457559 (EP '559), and U.S. Pat. No. 5,491,243 (US '243) and U.S. Pat. No. 6,541,668 provide synthetic routes for the preparation of duloxetine. US '269 describes the preparation of duloxetine by reacting (S)-(−)-N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine with fluoronaphtalene (Stage a), followed by demethylation with Phenyl chloroformate or trichloroethyl chloroformate (Stage b) and basic hydrolysis (Stage c) according the following scheme.

The conversion of duloxetine to its hydrochloride salt is described in U.S. Pat. No. 5,491,243 and in Wheeler W. J., et al, J. Label. Cpds. Radiopharm, 1995, 36, 312. In both cases the reactions are performed in ethyl acetate.

EP '559 discloses the conversion of DNT-Oxal to DNT-base with sodium hydroxide. The use of oxalic acid results in the formation of very toxic substances.

There is a need in the art for an improved synthetic process for the preparation of duloxetine HCl.

Stereochemical purity is of importance in the field of pharmaceuticals, where many of the most prescribed drugs exhibit chirality, and the two isomers exhibit different potency. Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. Therefore, there is a need to obtain the desired enantiomer of duloxetine HCl in high enantiomeric purity.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule of a compound, such as DNT-Di-p-toluoyl-L-tartarate, may give rise to a variety of crystalline forms, having distinct crystal structures and physical properties, such as melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides (S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine-Di-p-toluoyl-L-tartarate (DNT-L-pTTA) represented by the formula C₃₉H₃₉NO₉S and the structure

DNT-L-pTTA may also exist in a crystalline form. The crystalline form is characterized by data selected from: ¹H NMR (400 MHz, CDCl3 d6) δ(ppm): 8.26 (m, 1H), 7.99 (d, J=8.2 Hz, 4H), 7.81 (m, 1H), 7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.17 (m, 1H), 7.07 (d, J=3.2 Hz, 1H), 6.89 (t, J=3.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 5.88 (s, 2H), 5.79 (m, 1H), 3.20 (m, 2H), 2.75 (s, 6H), 2.58 (m, 2H), 2.37 (s, 6H); 13C {1H}NMR (100 MHz): δ 170.5, 165.7, 152.3, 143.6, 142.7, 134.5, 130.0, 128.9, 127.5, 126.9, 126.8, 126.3, 125.7, 125.5, 125.3, 125.0, 121.6, 121.0, 107.2, 73.3, 72.6, 54.6, 43.0, 38.6, 33.0, 21.5; and FAB MS: m/z 312 ([M−H]+, 100%).

In another embodiment, the present invention provides a crystalline form of DNT-L-pTTA, herein defined as Form 01, characterized by a powder XRD pattern having peaks at about 5.5°, 13.9°, 17.7°, 19.9°, and 22.8° 2θ±0.2° 2θ.

In another embodiment, the present invention provides a process for preparing DNT-L-pTTA, comprising providing a mixture of Di-p-toluoyl-L-tartaric acid and a solution of DNT in a solvent selected from a group consisting of C₁₋₈ alcohols, C₃₋₈ esters, C₂₋₈ ethers, C₃₋₈ ketones, C₆₋₁₂ aromatics hydrocarbons, and acetonitrile; maintaining the mixture until a precipitate is formed, and recovering the DNT-L-pTTA.

In another embodiment, the invention provides a process for preparing enantiomerically pure DNT, comprising combining DNT-L-pTTA, water, base, and toluene to obtain a two phase system, and separating the organic phase containing enantiomerically pure DNT and toluene.

The present invention further provides pharmaceutically acceptable salts of duloxetine prepared by obtaining DNT-L-pTTA, as described above, and converting the DNT-L-pTTA to pharmaceutically acceptable salts of duloxetine. Preferably, the DNT-L-pTTA is converted to duloxetine hydrochloride.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 illustrates the powder X-ray diffraction pattern for DNT-L-pTTA Form 01.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “DNT” or “DNT-base” refer to the compound (S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, having at least 2.3% (mol%) of the enantiomer R.

Wherein the DNT has less than about 2.3% of the enantiomer R, the DNT is “enantiomerically pure DNT”. Preferably, the enantiomerically pure DNT has less than 1.5% of the enantiomer R, more preferably less than 0.4% of the enantiomer R.

In one embodiment, the present invention provides (S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine-Di-p-toluoyl-L-tartarate (DNT-L-pTTA), represented by the formula C₃₉H₃₉NO₉S and the structure:

DNT-L-pTTA may also exist in a crystalline form. The crystalline form is characterized by data selected from: ¹H NMR (400 MHz, CDCl3 d6) δ(ppm): 8.26 (m, 1H), 7.99 (d, J=8.2 Hz, 4H), 7.81 (m, 1H), 7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.17 (m, 1H), 7.07 (d, J=3.2 Hz, 1H), 6.89 (t, J=3.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 5.88 (s, 2H), 5.79 (m, 1H), 3.20 (m, 2H), 2.75 (s, 6H), 2.58 (m, 2H), 2.37 (s, 6H); 13C {1H}NMR (100 MHz): δ 170.5, 165.7, 152.3, 143.6, 142.7, 134.5, 130.0, 128.9, 127.5, 126.9, 126.8, 126.3, 125.7, 125.5, 125.3, 125.0, 121.6, 121.0, 107.2, 73.3, 72.6, 54.6, 43.0, 38.6, 33.0, 21.5; and FAB MS: m/z 312 ([M−H]+, 100%).

In another embodiment, the present invention provides a crystalline form of DNT-L-pTTA, herein defined as Form 01, characterized by a powder XRD pattern having peaks at about 5.5°, 13.9°, 17.7°, 19.9°, and 22.8°2ν±0.2° 2θ. The crystalline form may be further characterized by an X-ray powder diffraction pattern having peaks at about 10.2°, 15.1°, 16.9°, 18.9°, and 24.2° 2θ±0.2° 2θ. The crystalline form may be further characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 1.

Preferably, the crystalline form 01 of DNT-L-pTTA has a maximum particle size of less than about 500 μm, more preferably, less than about 300 μm, more preferably, less than about 200 μm, more preferably, less than about 100 μm, and, most preferably, less than about 50 μm.

The particle size of DNT-L-pTTA crystalline forms may be measured by methods, including, but not limited to, sieves, sedimentation, electrozone sensing (coulter counter), microscopy, and Low Angle Laser Light Scattering (LALLS).

In another embodiment, the present invention provides a process for preparing DNT-L-pTTA, comprising providing a mixture of Di-p-toluoyl-L-tartaric acid and a solution of DNT in a solvent selected from the group consisting of C₁₋₈ alcohols, C₃₋₈ esters, C₂₋₈ ethers, C₃₋₈ ketones, C₆₋₁₂ aromatics hydrocarbons and, acetonitrile; maintaining the mixture until a precipitate is formed, and recovering the DNT-L-pTTA.

Preferably, the obtained DNT-L-pTTA is crystalline Form 01.

Preferably, the solvent is selected from a group consisting of C₄₋₆ alcohols, C₄₋₆ esters, C₄₋₆ ethers, and C₃₋₈ ketones, more preferably, the solvent is selected from a group consisting of n-BuOH, acetone, ethyl acetate, and MTBE.

Preferably, the mixture is maintained while stirring. More preferably, the mixture is maintained while stirring at about room temperature for about 1 hour.

DNT-L-pTTA may then be recovered by any method known in art, such as filtration and drying the precipitate, preferably at a temperature of from about room temperature to about 70° C., at a pressure below about 100 mmHg in a vacuum oven.

The process described above also decreases the level of the undesired R-enantiomer of DNT-L-pTTA, relative to the amount of DNT R-enantiomer in the original DNT, such that, where the solution of DNT contains a first molar amount of enantiomer R of DNT, and the precipitate contains a second molar amount of enantiomer R of DNT-L-pTTA, the second molar amount is less than the first molar amount.

Preferably the decrease is at least about 60%, more preferably, at least about 80%, even more preferably, at least about 90%, and, most preferably, at least about 99.8%. This process is capable of decreasing the level of the undesired R-enantiomer to below the detection limit.

In another embodiment, the invention provides a process for preparing enantiomerically pure DNT, comprising combining DNT-L-pTTA, water, base, and toluene to obtain a two phase system, and separating the organic phase containing enantiomerically pure DNT and toluene.

Preferably, the DNT-L-pTTA is crystalline Form 01.

In another embodiment, the invention provides pharmaceutically acceptable salts of duloxetine prepared by obtaining DNT-L-pTTA, as described above, and converting the DNT-L-pTTA to pharmaceutically acceptable salts of duloxetine.

Preferably, the DNT-L-pTTA is converted to duloxetine hydrochloride.

The DNT-L-pTTA used in this process is preferably the DNT-L-pTTA prepared, as described above. As such, it has a low content of the R-enantiomer, and, therefore, the duloxetine HCl obtained via this DNT-L-pTTA also has a decreased molar content of its R-enantiomer, relative to the molar amount found in duloxetine hydrochloride prepared with prior art methods.

The conversion of DNT-base to duloxetine HCl may be performed by any method known in the art, such as the one described in U.S. Pat. No. 5,491,243 or in co-pending U.S. application Ser. No. 11/318,365, filed Dec. 23, 2005, the contents of which are incorporated herein in their entirety by reference. The conversion may be performed by dissolving DNT-base in an organic solvent; adding alkyl chloroformate at a temperature of about 5° C. to less than about 80° C. to obtain duloxetine alkyl carbamate; combining the duloxetine alkyl carbamate with an organic solvent and a base; maintaining the reaction mixture at reflux temperatures for at least 1 to 3 hours; cooling, and adding water and an additional amount of an organic solvent; recovering duloxetine; combining the duloxetine with a solvent; adding hydrochloric acid until a pH of 3 to 4 is obtained; maintaining the reaction mixture to obtain a solid residue; and recovering duloxetine HCl.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the analysis of the duloxetine HCl and methods for preparing the duloxetine HCl of the invention.

It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Instruments

X-Ray powder diffraction (XRD) data was obtained using a Scintag X-ray powder diffractometer model X'TRA equipped with a Cu-tube solid state detector. A round standard aluminum sample holder with rough zero background quartz plate with a cavity of 25 (diameter)×0.5 mm (depth) was used. The scanning parameters included: range: 2° to 40° 2θ; scan mode: continuous scan; step size: 0.05 a rate of 5 deg/min.

Preparation of DNT-L-PTTA

Examples 1-4

A 6.2 g sample of di-p-toluoyl-L-tartaric acid was added to a solution of 5 g of DNT-base (2.3% enantiomer R, mol %) dissolved in 50 ml of an appropriate solvent, and the resulting mixture was stirred for about 1 hour. The resulting solid was filtered and washed with 10 ml of the appropriate solvent, and dried in a vacuum oven at 50° C. for 16 hours. The product was analyzed by XRD, and found to be form 01. Example Solvent % yield % enantiomer R 1 n-BuOH 79 1.45 2 Acetone 74 0.40 3 Ethyl acetate 85 1.61 4 MTBE 84 1.85 Preparation of enantiomerically pure DNT

Example 5

A 2 liter reactor equipped with a mechanical stirrer is charged with a mixture of 107 g DNT-L-pTTA, 600 ml water, 96 ml of a 22 percent solution of ammonium hydroxide, and 1 liter toluene. The mixture is stirred at 25° C. for 20-30 mintues, and the organic phase is separated and washed with water (3×300 ml). The toluene solution of DNT-base is used directly in the conversion to duloxetine HCl, without evaporation.

While it is apparent that the invention disclosed herein is well calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention. 

1. (S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine-Di-p-toluoyl-L-tartarate (DNT-L-pTTA).
 2. The DNT-L-pTTA of claim 1, characterized by data selected from: ¹H NMR (400 MHz, CDCl3 d6) δ(ppm): 8.26 (m, 1H), 7.99 (d, J=8.2 Hz, 4H), 7.81 (m, 1H), 7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.17 (m, 1H), 7.07 (d, J=3.2 Hz, 1H), 6.89 (t, J=3.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 5.88 (s, 2H), 5.79 (m, 1H), 3.20 (m, 2H), 2.75 (s, 6H), 2.58 (m, 2H), 2.37 (s, 6H); 13C {1H}NMR (100 MHz): δ 170.5, 165.7, 152.3, 143.6, 142.7, 134.5, 130.0, 128.9, 127.5, 126.9, 126.8, 126.3, 125.7, 125.5, 125.3, 125.0, 121.6, 121.0, 107.2, 73.3, 72.6, 54.6, 43.0, 38.6, 33.0, 21.5; and FAB MS: m/z 312 ([M−H]+, 100%).
 3. A crystalline form of DNT-L-pTTA, characterized by a powder XRD pattern having peaks at about 5.5°, 13.9°, 17.7°, 19.9°, and 22.8° 2θ±0.2° 2θ.
 4. The crystalline form of claim 3, further characterized by a powder XRD pattern having peaks at about 10.2°, 15.1°, 16.9°, 18.9°, and 24.2° 2θ±0.2° 2θ.
 5. The crystalline form of claim 4, characterized by an X-ray powder diffraction pattern substantially as depicted in FIG.
 1. 6. A process for preparing the DNT-L-pTTA of claim 1, comprising a. providing a mixture of Di-p-toluoyl-L-tartaric acid and a solution of DNT in a solvent selected from a group consisting of C₁₋₈ alcohols, C₃₋₈ esters, C₂₋₈ ethers, C₃₋₈ ketones, C₆₋₁₂ aromatics hydrocarbons and acetonitrile; b. maintaining the mixture until a precipitate is formed; and c. recovering the DNT-L-pTTA.
 7. The process of claim 6, wherein the DNT-L-pTTA obtained is a crystalline form of DNT-L-pTTA, characterized by a powder XRD pattern having peaks at about 5.5°, 13.9°, 17.7°, 19.9°, and 22.8° 2θ±0.2° 2θ.
 8. The process of claim 6, wherein the solvent is selected from a group consisting of C₄₋₆ alcohols, C₄₋₆ esters, C₄₋₆ ethers, and C₃₋₈ ketones.
 9. The process of claim 8, wherein the solvent is selected from a group consisting of n-BuOH, acetone, ethyl acetate, and MTBE.
 10. The process of claim 6, wherein the mixture is maintained while stirring at about room temperature for about 1 hour.
 11. The process of claim 6, wherein the solution of DNT contains a first molar amount of enantiomer R of DNT, and the precipitate contains a second molar amount of enantiomer R of DNT-L-pTTA, and wherein the second molar amount is less than the first molar amount.
 12. The process of claim 11, wherein the second molar amount is at least about 60 percent less than the first molar amount.
 13. The process of claim 12, wherein the second molar amount is at least about 80 percent less than the first molar amount.
 14. The process of claim 13, wherein the second molar amount is at least about 90 percent less than the first molar amount.
 15. The process of claim 14, wherein the second molar amount is at least about 99.8 percent less than the first molar amount.
 16. A process for preparing enantiomerically pure DNT, comprising: a. combining the DNT-L-pTTA of claim 1, water, base, and toluene to obtain a two phase system; and b. separating the organic phase containing enantiomerically pure DNT and toluene.
 17. The process of claim 16, wherein the DNT-L-pTTA is a crystalline form of DNT-L-pTTA, characterized by a powder XRD pattern having peaks at about 5.5°, 13.9°, 17.7°, 19.9°, and 22.8° 2θ±0.2° 2θ.
 18. Pharmaceutically acceptable salts of duloxetine prepared by obtaining the DNT-L-pTTA of claim 1, and converting the DNT-L-pTTA to pharmaceutically acceptable salts of duloxetine.
 19. The process of claim 18, wherein the DNT-L-pTTA is converted to duloxetine hydrochloride. 